1. Field of the Invention
The invention relates to a sustained-release preparation which releases a physiologically active substance for long periods of time.
2. Description of the Prior Art
To prepare sustained release type drug delivery systems (DDS), there are usually used various methods, including coacervation, emulsion phase separation, spray drying-dependent encapsulation, and solvent evaporation in organic or water phase. Of them, the solvent evaporation in water phase is the most extensively used, which is largely divided into two techniques: W/O/W (water/oil/water) double emulsification and O/W (oil/water) simple emulsification.
The W/O/W technique is usually used for the encapsulation of water-soluble drugs such as peptides or proteins. In this technique, a water-soluble drug is dissolved in water and this aqueous layer is dispersed in an organic layer containing a biodegradable polymer, so as to give a primary emulsion (water in oil). Again, this primary emulsion is dispersed in water. The O/W technique, which is usually used to capsulate lipid-soluble drugs, can be conducted by dissolving a drug and a biodegradable polymeric excipient in an organic solvent or an inorganic solvent mixture and dispersing the solution in an aqueous phase. In both of the two, the solubility of the polymer decreases as the organic solvent is removed through extraction or evaporation in the course of dispersing an oil phase of the polymer in an aqueous phase. As a result, the polymer is solidified to form microparticles. Generally, compared with those obtained by the O/W technique, the microparticles obtained by the W/O/W technique are of a more porous structure with higher surface areas so that they are high in the initial release rate of drugs.
The release time period of such sustained release microparticles is determined largely by physical and chemical properties of polymers, compositions of solvents, and kinds and concentrations of emulsifiers. Of these determinant factors, the most important are the physical and chemical properties of polymers, including chemical compositions, molecular weights, and hydrophilicity. For example, poly(lactide-co-glycolide) (PLGA), a polymer consisting of lactide and glycolide with a different molar ratio therebetween, is degraded at low rates as the lactide is increased in molar ratio or molecular weight. In this case, polymers which are higher in lactide content or greater in molecular weight lead to longer release time periods. However, where the polymer is degraded for an extended period of time, the microparticle hardly releases its encapsulated drug in some points of the early or intermediate stage. Therefore, using one polymer in preparing sustained release microparticles able to continuously release drugs for desired periods of time (e.g., one, two, three, six months or longer) requires extensive effort and time. On account of this problem, research has been directed to the employment of combinations of quickly and slowly degradable polymers in encapsulating drugs. From the quantity of the drug released from the microparticles made of the combined polymers, however, the release rate of the drug from the microparticles cannot be determined accurately. Under the coexistence of at least two different polymers in one microparticle, the more slowly degradable polymer tends to be degraded at a faster rate owing to the degradation products of the faster degradable polymer than under its sole existence. In result, the release rate of drugs in the body is also affected by the faster degradable polymer and thus, different from the average value of the release rates of drugs encapsulated in individual polymers.
To circumvent this problem, the same active ingredients are encapsulated in at least two individual polymers which are different in degradation rate from each other and the microcapsules are combined at appropriate ratios to give a microcapsule dosage formulation which can release the active ingredients for a desired period of time, as disclosed in U.S. Pat. No. 4,897,268. However, this technique is cumbersome in that two or more types of microcapsules are needed for one drug dosage form and thus is unfavorable economically.
It is an object of the present invention to provide a method for preparing a sustained drug release formulation composed of various microparticles which retain their drug release properties in their integrity, whereby the release period of time of the formulation can be easy to expect and be controlled by varying compositions and molecular weights of polymers, compositions and concentrations of solvents, and kinds and amounts of additives.
It is another object of the present invention to provide a sustained drug release formulation which can release drugs of interest for a desired period of time.
In accordance with the present invention, a sustained drug release formulation can be prepared using a multi-emulsion process, which comprises the steps of: dissolving or dispersing a drug in each of at least two oils to give at least two primary oil phases or emulsions, each containing a biodegradable polymer; dispersing the at least two primary oil phases or emulsions in one aqueous phase, synchronously or in succession; and removing the organic solvents from the drug-dispersed solution to produce microparticles.
In the present invention, LHRH analogues can be encapsulated in an excipient made of a biodegradable aliphatic polyester and continuously released in vivo for a desired period of time.